The project consists of a series of clinical trials evaluating the clinical efficacy and safety of experimental therapeutic agents for the control of acute pain and perioperative apprehension in ambulatory patients undergoing minor surgical procedures. The surgical removal of impacted third molars serves as a model for minor surgical procedures with associated intraoperative and postoperative pain and perioperative apprehension. All studies are double-blind with randomly allocated, parallel treatment groups and multiple dependent measures of therapeutic efficacy and clinical safety. A recent study evaluated the analgesic efficacy of two anithistamine drugs in comparison to ibuprofen and placebo. Terfenadine, a H1 histamine receptor blocker, and ranitidine, a H2 histamine receptor blocker, were administered one hour prior to oral surgery and the onset and severity of postoperative pain monitored for four hours postoperatively. Final analysis demonstrated that dependent measures for analgeisa were sensitive to the effects of the positive control, 400 mg of ibuprofen, but that the two antihistamines could not be differentiated from the effects of placebo. These data indicate that pretreatment with a single dose of a histamine receptor antagonist does not produce analgesia in the oral surgery model, suggesting that antihistamines which act primarily at peripheral sites are devoid of analgesic activity. A current study is evaluating the combination of ibuprofen and oxycodone to define an analgesic combination which results in additive analgesia for the management of pain not responsive to the use of a single agent such as ibuprofen and related drugs. Interim evaluation suggests that the highest dose of oxycodone is resulting in additive analgesia in comparison to ibuprofen alone or ibuprofen alone or ibuprofen plus lower doses of oxycodone. Demonstration of an additive effect for an opioid-nonsteroidal anti-inflmmatory drug combination may provide a basis for the management of severe acute pain with an oral drug combination.